Recently our understanding of the molecular mechanisms governing the development of the brain has been facilitated by genetic approaches in human and mouse that have identified several genes and protein products required for neocortical development and neuronal migration. Many of these genes and protein products have been placed into three major functional pathways, based on genetic, biochemical and cell biological studies in mouse models: the RELN pathway, the Cdk5/p35 pathway and the LIS1 pathway. Recent studies from this program project have identified some important cross-talk between these three pathways. However, there are several critical gaps in our understanding. First, it is unknown if these pathways and interactions regulate exclusively neuronal migration or other processes involved in brain development such as neurogenesis and survival. Second, the manner and degree in which these various components and signaling pathways are interconnected are not known. Finally, the relationships of OCX to the three major pathways of neuronal migration are unknown. It is critical to determine the integration of the gene products and their signaling pathways during neuronal migration for a more comprehensive understanding of the molecular intricacies that govern neocortical development. Therefore, we propose to investigate the integration of these pathways by the following Specific Aims: Aim 1. Test the hypothesis that LIS1 has several important functions during brain development and in the adult by examining the dosage dependent effects of LIS1 during neurogenesis, neuronal migration, cell survival and adult neuronal function in vivo. Based on our published and preliminary data, we predict that LIS1 is critical for processes at all stages of brain development, and even in the postmitotic adult brain, although not in non-neuronal somatic tissues. Aim 2 Test the hypothesis that the phosphorylation of NUDEL by Cdk5/p35 and binding to 14-3-3epsilon are critical for neuronal development and migration in vivo by producing specific Cdk5 phosphorylation site mutants in mice by BAG transgenesis. Aim 3 Test the hypothesis that OCX is part of the LIS1 pathway. Based on our preliminary data, we predict that with LIS1, OCX plays a role in the regulation of dynein motor function, and that regulation of OCX activity via phosphorylation by Cdk5/p35 may be analogous to NUDEL regulation.